Project Summary (Research Project 2) Type 2 diabetes mellitus (T2DM) is a progressive disease with many patients requiring insulin therapy. Treatment of patients with T2DM is challenging and many such patients remain uncontrolled, despite a high dosage of insulin, which itself tends to lead to weight gain. Tackling insulin resistance (IR) is critically important in the treatment of patients with T2DM, but effective treatment options are limited. Recent studies suggest that chronic inflammation, mediated by the IKKb/NF-kB pathway, may be implicated in the pathogenesis of IR and may provide new targets for its reversal. Salsalate (Disalcid) is a prodrug form of salicylate. The Targeting INflammation using SALsalate for Type 2 Diabetes Stage II (TINSAL-T2D) trial demonstrated the efficacy and safety of oral salsalate, given at a dose of 3.5 gm/day, in improving glycemic control in patients with T2DM who were not using insulin. Salsalate also suppresses inflammatory markers and may have beneficial effects on cardiovascular disease (CVD) risk factors. The benefit and safety of adjuvant therapy with salsalate in patients with T2DM using insulin are unknown. The efficacy of salsalate on glycated hemoglobin (HbA1c), insulin resistance, markers of inflammation and beta cell function has not been studied in such patients. Our hypothesis is that treatment with salsalate 3.5 gm/day will provide additional glycemic control in patients with T2DM on insulin and will improve markers of inflammation, beta cell function and surrogate markers of CVD risk. We propose to test this hypothesis by conducting a randomized, double-blind, placebo-controlled trial with the following specific aims: Determine whether the addition of oral salsalate, at a dose of 3.5 gm/day, in patients with T2DM on insulin therapy leads to improvement in: 1. glycemic control (HbA1c); 2. markers of inflammation, such as white cell count, high-sensitivity C-reactive protein, free fatty acids, adiponectin, interleukin-6, and serum uric acid, and 3. insulin sensitivity and beta cell function, based on the results of a mixed meal tolerance test with minimal model assessment. In addition, we will test for differences in quality of life using SF36 surveys; and differences in other CVD risk factors, including lipids and endothelial function and vascular compliance using noninvasive testing (EndoPAT). One hundred and forty patients with uncontrolled T2DM despite insulin therapy will be randomized to receive salsalate or placebo. We anticipate 90% statistical power to detect a 0.5% difference in HbA1c change between the salsalate treatment and placebo control groups over a 6 month period of intervention. The study will confirm proof of concept and provide important insight into the safety and efficacy of oral salsalate use in patients with T2DM on insulin therapy. The proposed COBRE program will provide the junior faculty investigator with the protected-time and funding necessary to conduct high quality clinical research and help her transition into a successful competitive independent NIH- funded investigator.